Methyl-lysine readers PHF20 and PHF20L1 define two distinct gene expression-regulating NSL complexes

Area of Science:

• Biochemistry
• Molecular Biology
• Epigenetics

Background:

• Plant homeodomain finger protein 20 (PHF20) and PHF20-like protein 1 (PHF20L1) are methyl-lysine readers and components of the nonspecific lethal (NSL) complex.
• The NSL complex regulates gene expression via histone acetyltransferase activity.
• The coexistence and distinct functions of PHF20 and PHF20L1 within the NSL complex were not previously established.

Purpose of the Study:

• To biochemically and functionally characterize PHF20 and PHF20L1 within the NSL complex.
• To investigate the roles of PHF20 and PHF20L1 in NSL complex integrity and transcriptional regulation.
• To determine if PHF20 and PHF20L1 exist in separate NSL complexes.

Main Methods:

• Mass spectrometry to identify protein complexes.
• Genome-wide chromatin analysis to map protein binding sites.
• Protein-domain mapping to determine functional regions.

Main Results:

• Two distinct NSL complexes were identified, each containing either PHF20 or PHF20L1 exclusively.
• C-terminal domains are crucial for NSL complex formation, while Tudor 2 domains mediate chromatin binding.
• PHF20 and PHF20L1 bind to promoters of highly expressed genes, but their deletion does not affect gene expression or NSL recruitment, suggesting compensatory mechanisms.

Conclusions:

• The study reveals two distinct NSL complexes, challenging the existing model of PHF20 and PHF20L1 co-occurrence.
• Identifies specific protein domains essential for NSL complex assembly and chromatin interaction.
• Suggests alternative regulatory pathways compensate for PHF20/PHF20L1 loss in maintaining gene expression, paving the way for studying their differential roles in health and disease.